Disorders of Sexual Differentiation

Question 1

Gonadal Dysgenesis

Answer 1

Sexual differentiation is incomplete. Usually
missing SRY in male, or partial or complete deletion of second X in
female. Also used as a general description of abnormal development of
the gonads.

Question 2

Sex Reversal

Answer 2

Phenotype does not match genotype, ie may be male
genotypically but externally look like a female.

Question 3

Intersex

Answer 3

Have some components of both tracts or have ambiguous
genitalia. Sex of infant difficult to determine.
Patients prefer to be known as someone with a ‘disorder of sexual differentiation’ or DSD.
Terms such as ‘pseudohermaphrodite’ and, ‘testicular feminisation’ are
now obsolete.

Question 4

XY individual, testosterone is made but has no effect

Answer 4

Androgen Insensitivity syndrome (AIS)

Question 5

AIS- characteristics

Answer 5

Individual is XY (male)
Testosterone is made but has no effect – androgen receptor is insensitive
Normally there is a mutation in the androgen receptor

Will have SRY and production of sertoli cells
The testes will from and produce AMH -> so the Mullerian ducts regress
Will produce Leydig cells that produce testosterone.
This testosterone will be converted into DHT by 5-a-reductase
BUT there is no differentiation of the wolffian ducts
As androgen receptor is insensitive to both testosterone and DHT (same receptor)
There is no external male genitalia
Will look feminine

Question 6

Complete AIS

Answer 6

incidence 1:20,000 (46XY)

Undescended testes.

No uterus or fallopian tubes

External genitalia appear female - abbreviated blind vaginal pouch.

Usually present with primary amenorrhoea. Lack of body hair is a clue.

Ultrasound scan and karyotype will show male levels of androgens.

Hormonal puberty may be feminizing without intervention due to aromatization of endogenous androgens to estrogens. Lacking response to androgen.

Sex assignment and rearing almost always female.

Differentiation of gender role and identity usually feminine. In adulthood, sexuality often conforms to typical heterosexual female expectations.

Question 7

Partial AIS (incidence unknown- spectrum (46XY))- MORE COMMON

Answer 7

Spectrum of phenotypes including almost normal female external genitalia through ambiguous genitalia (perineoscrotal hypospadias, microphallus, cryptorchidism).
Minor genital deviations go unnoticed or may be surgically repaired.
At puberty development of male secondary characteristics may not be very pronounced. In some cases pubertal gynecomastia (androgen/estrogen ratio) or ambiguous genitalia surgically corrected. Androgen therapy in some cases.
Sometimes there is a small amount of testosterone before puberty, and it is not enough to masculinise the external genitalia. But then a puberty the testosterone levels rise a lot and may be just enough to pass the threshold for the genitalia to start to look masculine.
Majority of individuals develop an identity commensurate with their assigned gender - around 20% desire to change gender usually in adolescence or adulthood.

Question 8

Persistent Mullerian Duct Syndrome

Answer 8

An XY male is unable to make or respond to AMH in utero
Either a defect in the AMH gene or defect in the AMH receptor

XY -> SRY -> Testes -> Get Sertoli cells BUT:
Testes will form and either fail to make AMH or the AMH receptor is absent
Therefore the Mullerian ducts remain
But will still have Leydig cells -> testosterone so: There is differentiation of the wolffian ducts and masculinised external genitalia (plus Mullerian structures)

Question 9

Persistent Mullerian Duct Syndrome- Type I vs Type II

Answer 9

PMDS type I usually results from mutations of the gene for AMH on chromosome 19.
PMDS type II results from mutations of the gene for the AMH receptor (AMH-RII) on chromosome 12.
Both autosomal recessive conditions with expression usually limited to XY offspring.
Is an autosomal recessive condition:

Question 10

PMDS common presentation

Answer 10

• 60–70% of cases have intra-abdominal Mullerian structures and testes in a position simulating that of the ovaries
• 20–30% have one testis in a hernial sac or scrotum together with Mullerian structures.
• 10% have both testes located in the same hernial sac (transverse testicular ectopia) along with the uterine tubes and/or uterine structures.
• All have increased risk of malignant transformation

Question 11

PMDS treatments

Answer 11

• Surgery (orchiopexy) to retrieve the testes and position them in the scrotum. If testes cannot be retrieved, testosterone replacement at puberty is an option.
• Removal of uterus dissection of Müllerian tissue away from the vas deferens/epididymis.
• Laparoscopic hysterectomy may prevent the occurrences of neoplastic tissue formation.

Question 12

XY individual, testosterone is made but not DHT

Answer 12

5-α-reductase deficiency

Question 13

5-α-reductase deficiency

Answer 13

XY -> SRY = testes

Testes form and make AMH so Mullerian ducts regress.

Will get Leydig cells -> testosterone -> Wolffian ducts develop = normal internal genitalia

BUT do not have 5-a-reductase in the genital skin (not functioning-mutation) -> DHT is not made = No male external genitalia

Undescended testes, external genitalia will appear female/ambiguous genitalia

Question 14

5-α-reductase deficiency- incidence varies enormously (46XY)

Answer 14

Testes form, AMH acts, testosterone acts. Internal structures form. External male structures do not fully develop.
May appear mainly female or may have ambiguous genitalia such as labioscrotal folds or clitoridean penis.
The degree of the enzyme block varies and so therefore does the presentation.
Eg the 5-a-reductase may have a low affinity or may be completely absent
Need to assess potential of patient as high testosterone level which will occur at adrenarche, and puberty may be enough to pass the threshold and induce virilisation.
So may start off with mainly female/ambiguous genitalia, but then at puberty when testosterone levels rise, it may be enough to produce enough DHT to masculinise the external genitalia.
Both testosterone and dihydrotestosterone (DHT) are capable of masculinising the brain in non-human primates so some brain masculinisation in utero possible with this condition.

Question 15

Turners Syndrome

Answer 15

Individual is 45 XO (one X)
So have all pairs of chromosomes but no X
Will have ovaries – as there is no Y, therefore no SRY
Will have Mullerian ducts - as there is no AMH
Will NOT have wolffian ducts – as there is no sertoli cells so no testosterone
Will have Female external genitalia

Question 16

Turner Syndrome (incidence 1:3000)

Answer 16

XO have failure of ovarian function. ‘Streak’ ovaries = ovarian dysgenesis - illustrates that we need two X’s for ovarian development.
Ovaries are small and have streaks in them which can impact fertility
Uterus and tubes are present, may be small or other defects in growth and development. Wide spectrum of phenotypic disorders and severity.
May be fertile, many have mosaicism. Female gender.
Need hormone support of bones and uterus.

In females, you have 2 X chromosomes but in any given cell, only one is expressed, the other one is repressed. Overall, they are expressed equally. BUT there are some genes on the repressed X that are being made, which is important for normal development. Therefore, you need both X present.

There is large variation in the presentation of Turner syndrome as it depends when the second X is lost.
If it is lost at one of the early cell divisions in the developing embryo, then every cell in the body will have one X
But if it happens later during embryogenesis, only the descendants of the cell where it was lost will have one X.

Question 17

XX female exposed to high levels of androgens in utero

Answer 17

Congenital adrenal hyperplasia (most common cause: 1:15,000)

Question 18

Steroidogenesis

Answer 18

Cholesterol – 3 six sided rings, a 5 sided ring and a carbon chain
All the steroids are cholesterol with the carbon chain removed (22-27)

If you remove the chain from carbon 22-27, you get the progestogens that have 21 carbons
The only difference between the progestagens are the placement of the hydroxyl and oxygen groups

If you remove 2 more carbons, so you have 19 in total, you have the androgens.
Again the only difference between the androgens are the oxygen and the OH.

If you remove another carbon so you have 18 carbons you have the estrogens
There are three estrogens depending on the OH groups:
Estradiol has 2 OH groups (E2)
Estrone has 1 OH group (E1)
Estriol has 3 OH groups (E3)

The enzyme that removes the one carbon off the androgens -> estrogens is called aromatase.

These three sex steroids (progestogen, androgens and estrogens) are made in the testes and ovary.

The adrenal glands are on the top of the kidney and importantly produce aldosterone and cortisol. They are both produced from progestogens and have 21 carbons.
You need aldosterone to recover salt and water as part of the RAAS system.
Cortisol – important in stress and glucose response.

Question 19

Congenital Adrenal Hyperplasia

Answer 19

21-Hydrooxylase
Baby is trying to make aldosterone in the adrenal glands
It takes in cholesterol, removes the carbon chain to more progestogen
It then needs to add an OH group
BUT the 21-hydroxylase enzyme is missing, so it cannot make aldosterone or cortisol.

Failure to synthesise cortisol

Question 20

CAH- HPG axia

Answer 20

The hypothalamus produces corticotropin releasing hormone
This stimulates the pituitary to secrete ACTH

ACTH stimulates the adrenal glands to make cortisol

Adrenocorticotropic hormone
Stimulates rapid uptake of cholesterol into the adrenal cortex. Upregulates cholesterol side-chain cleavage enzyme (P450scc). Increases glucocorticoid secretion.

Question 21

If you cannot make aldosterone or cortisol in congenital adrenal hyperplasia:

Answer 21

You won’t have the negative feedback from cortisol.
So without negative feedback you will get an increase in corticotropin releasing hormone CRH, and increased amounts of ACTH.
This is due to the enzyme 21-hydroxylase missing.

Question 22

Effect of increased ACTH on androgens- why does this lead to enlarged adrenal glands

Answer 22

The increase in ACTH trying to drive the production of cortisol causes an upregulation in cholesterol side chain cleavage enzyme. This will in turn cause the progestogen level to rise.
BUT the progestogens cannot be converted into aldosterone and cortisol so it is instead converted into androgens.
This causes androgen levels to rise and build up

If you did an ultrasound on a baby with CAH, you will see that the adrenal glands are enlarged as they are trying to produce cortisol and aldosterone.

Question 23

CAH- explained

Answer 23

In a baby girl XX, there is no SRY
So will make an ovary
There is no AMH -> so Mullerian ducts remain = internal female genitalia.
BUT as the adrenal glands are making androgens
5-a-reductase is present -> so the androgens will be converted into DHT
This will lead to masculinised external genitalia
BUT the androgen levels are not normally high enough to rescue the wolffian ducts.

Question 24

Consequences of CAH

Answer 24

Congenital adrenal hyperplasia (CAH) - 1:15,000 (XX).
Completeness of the enzyme block varies. May have developed Wolffian structures and ambiguous masculinised external genitalia or hirsutism .
Early studies suggested that XX patients assigned as girls developed female gender identity, but with more masculine childhood behaviour and lower maternal interest as adults.
Also in CAH need to be aware of possibility of ‘salt-wasting’ due to lack of aldosterone, this can be lethal.
Treatment with glucocorticoids to correct feedbac

Question 25

Summary

Answer 25

Correct sexual differentiation requires genetic, anatomical and endocrine components.

Disorders are rare, but have allowed scientists to understand the requirements for normal development.

Diagnosis and treatment of conditions of abnormal sexual differentiation requires a specialist team.

Long-term functioning of the person now the primary issue rather than immediate ‘corrective’ surgery.